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Transposon Mutagenesis Identifies Genes Essential for Plasmodium

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Transposon Mutagenesis Identifies Genes Essential for Plasmodium Transposon mutagenesis identifies genes essential PNAS PLUS for Plasmodium falciparum gametocytogenesis Hiromi Ikadaia,1,2, Kathryn Shaw Salibaa,2,3, Stefan M. Kanzokb, Kyle J. McLeana, Takeshi Q. Tanakab,4, Jun Caoa,5, Kim C. Williamsonb, and Marcelo Jacobs-Lorenaa,6 aDepartment of Molecular Microbiology and Immunology, Johns Hopkins Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205; and bDepartment of Biology, Loyola University, Chicago, IL 60660 Edited by Alexander S. Raikhel, University of California, Riverside, CA, and approved March 12, 2013 (received for review October 15, 2012) Gametocytes are essential for Plasmodium transmission, but little poststage I development will ensue, where the stage I gametocyte is known about the mechanisms that lead to their formation. Us- will undergo a maturation process over an ∼5- to 7-d period, ing piggyBac transposon-mediated insertional mutagenesis, we resulting in a mature stage V female or male gametocyte. screened for parasites that no longer form mature gametocytes, Very little is known about the molecular mechanisms governing which led to the isolation of 29 clones (insertional gametocyte- the commitment of the dividing parasites to gametocytogenesis or deficient mutants) that fail to form mature gametocytes. Additional about the genes required for gametocyte commitment and de- analysis revealed 16 genes putatively responsible for the loss of velopment. Microarray experiments with early or mature game- gametocytogenesis, none of which has been previously implicated tocytes revealed 246 gametocyte-specific genes (9). The majority in gametocytogenesis. Transcriptional profiling and detection of (∼75%) encodes genes of unknown function. A small number an early stage gametocyte antigen determined that a subset of of these gametocyte-specific genes—Pfs16, Pfg27, Pfmdv1/peg3, these mutants arrests development at stage I or in early stage II Pf11.1, Pfs230, and Pfg377—have been knocked out. However, in gametocytes, likely representing genes involved in gametocyte every case, mutant parasites still formed mature gametocytes, maturation. The remaining mutants seem to arrest before forma- albeit in lower numbers (11–16). To date, no genes essential for tion of stage I gametocytes and may represent genes involved in gametocytogenesis have been identified. commitment to the gametocyte lineage. We took a forward genetic approach to identify genes required for the formation of mature gametocytes. Using genome-wide MICROBIOLOGY malaria | piggyBac insertional mutagenesis | gametocyte development | piggyBac transposon-mediated insertional mutagenesis, we iso- Plasmodium genetics lated 29 gametocyte-negative clones termed insertional game- tocyte-deficient mutants (IGMs). Of 29 IGMs, 22 IGMs had alaria remains the most devastating parasitic disease, kill- a single transposon insertion at 16 unique loci, and none of them Ming an estimated 1 million people every year. With ∼50% had previously been implicated in gametocytogenesis. Here, we of the world’s population at risk, novel interventions are des- report on the initial characterization of these IGMs. perately needed (1). The disease is caused by the asexual mul- tiplication of the protozoan parasite Plasmodium in the blood Results of its mammalian host, and transmission occurs by Anopheles Isolation of Gametocyte-Deficient Mutant Parasites by piggyBac mosquitoes. Although the vast majority of the parasites undergo Transposon Mutagenesis. We used piggyBac transposon mutagen- asexual replication, in response to ill-defined environmental esis (17, 18) to identify genes required for P. falciparum game- stimuli, a small subset commits instead to sexual differentiation tocytogenesis. Parasites used for the screen (hereafter referred and forms gametocytes (2). After feeding on an infected host, to as parental) contained a plasmid encoding a GFP gene driven gametocytes are the only form of the parasite that is able to by the Pfs28 promoter, which is active only in late stage male and survive and develop in the mosquito vector. Thus, gametocytes female gametocytes (stages IV and V) (19). Any mutant derived are required for transmission of Plasmodium. However, the bi- from this line that is impaired in mature gametocyte formation ology of gametocyte formation is poorly understood. will not produce fluorescent parasites on induction of game- Gametocytogenesis (gametocyte formation) of the human tocytogenesis. Parental parasites were transfected with a mixture malaria parasite P. falciparum can be broken down into three of two plasmids: one plasmid carrying a drug-resistant marker steps: commitment, prestage I gametocyte development, and poststage I gametocyte development. Early studies have shown that all merozoites from a single schizont follow either asexual or sexual fate (3, 4), and those merozoites that commit to sexual Author contributions: H.I., K.S.S., S.M.K., K.J.M., T.Q.T., J.C., K.C.W., and M.J.-L. designed differentiation form exclusively male or exclusively female ga- research; H.I., K.S.S., S.M.K., K.J.M., T.Q.T., J.C., and K.C.W. performed research; K.C.W. contributed new reagents/analytic tools; H.I., K.S.S., S.M.K., K.J.M., T.Q.T., J.C., K.C.W., and metocytes (5, 6). These observations suggest the existence of a M.J.-L. analyzed data; and H.I., K.S.S., K.J.M., and M.J.-L. wrote the paper. defined gene expression pathway leading to the commitment to The authors declare no conflict of interest. gametocytogenesis that probably acts before DNA synthesis and This article is a PNAS Direct Submission. nuclear division of the sexually committed schizont (7). More- 1Present address: Department of Veterinary Medicine, School of Veterinary Medicine and over, the extent of gametocyte production by a particular parasite Animal Sciences, Kitasato University, Towada, Aomori Prefecture 034-8628 35-1, Japan. strain can be influenced by the parasite’s environment (reviewed 2H.I. and K.S.S. contributed equally to this work. in ref. 7). 3Present address: Department of Immunology and Infectious Diseases, Harvard School of After the parasite commits to gametocytogenesis, it begins Public Health, Boston, MA 02115. prestage I development; the committed parasite undergoes sexual 4Present address: Laboratory of Malaria and Vector Research, National Institute of Allergy schizogony, producing sexually committed merozoites that, on and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892. release from the host red blood cell, invade fresh erythrocytes, 5Present address: Malaria Department, Jiangsu Institute of Parasitic Diseases, Wuxi, resulting in the formation of a sexually committed ring. Over the Jiangsu 214064, People’s Republic of China. next ∼24–30 h, this committed ring stage parasite differentiates 6To whom correspondence should be addressed. E-mail: [email protected]. fi into a morphologically and molecularly identi able stage I ga- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. metocyte (8–10). After the stage I gametocyte has formed, the 1073/pnas.1217712110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1217712110 PNAS Early Edition | 1of9 Downloaded by guest on September 29, 2021 flanked by the piggyBac inverted terminal repeats, and the other by semiquantitative RT-PCR (Fig. S1).ForIGMsthathadinser- plasmid containing a helper transposase. Between one and four tions outside the coding region, mRNA abundance of both flanking generations posttransfection, parasites were cloned in individual genes was assayed. In all cases, mRNA abundance of only one of wells of 96-well plates and subjected to selection in the presence two genes was affected (Table 1 and Fig. S1). The gene with the of drug followed by growth in the absence of drug to promote the lower abundance is presumed to be the affected gene. loss of nonintegrated plasmids. Each clone was then screened for We also verified the expression pattern of each of 16 genes in the ability to produce fluorescent gametocytes. Clones that did the parental line (Fig. S2). In all cases, the mRNA expression not form gametocytes were tested three additional times by ab- profiles closely matched those profiles previously reported (20). sence of both fluorescent gametocytes and gametocytes in Giemsa- The majority of the genes identified were unannotated in the stained smears. From three independent transfection experiments, 3D7 genome. We used extensive BLAST searches (21) and pair- 189 drug-resistant clones were isolated, of which 29 (∼15%) clones wise comparisons by hidden Markov models on HHPred (22) to failed to form gametocytes (Fig. 1A). These 29 clones (IGMs) were determine remote homologs and functional domains to assign analyzed by Southern blot analysis and PCR to detect episomal putative identities to all 16 genes (Table 1). plasmids (Fig. 1 B and C and Table S1). Of 29 IGMs, 22 IGMs had single insertions, and only these IGMs were further characterized. Episomal Complementation Restores Gametocytogenesis to 5 of 22 IGMs. Because P. falciparum can spontaneously lose the ability to Identification of the Genes Disrupted by piggyBac Insertion. The sites produce gametocytes in vitro (23, 24) and cloning of P. falcipa- of transposon insertion in the IGMs were identified by inverse rum 3D7 was previously shown to produce gametocyte-negative PCR (Table S2). Sequence analysis revealed that insertion clones (25), it was important to confirm that the piggyBac in- events in 22 IGMs with single piggyBac elements occurred at
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